1Abhijeet Welankiwar*, Sushant tope.
1Government College of pharmacy
kathora naka Amravati (Maharashtra) 444604.
The validation is a Fundamental segment that supports to a commitment of company towards quality assurance. It also assures that product meets its predetermined quality specification and quality characteristics. Validation of individual step of manufacturing is called as process validation. Here this article concerns with the process validation of tablet dosage form which has a numerous advantages over other dosage forms. The objective is to present a review and to discuss aspects of validation in terms of pharmaceutical unit operations; that is, those individual technical operations that comprise the various steps involved in product design and evaluation.
REFERENCE ID: PHARMATUTOR-ART-1760
As per USFDA Process validation is “establishing documented evidence which provides high degree of assurance that a specific process will consistently produce a product meeting its predetermined Quality specifications and Quality characteristics”. The process validation is of 4 Types: -
1) Prospective validation.
2) Concurrent validation.
3) Retrospective validation.
1) Prospective validation: - In prospective validation the validation protocol is executed before the process is put into the commercial use. During the product development stage the production process should be broken down into individual steps. Each step should be evaluated on the basis of Experience or theoretical considerations to determine the critical parameters that may affect the quality of finished product.
2) Concurrent validation: - It is similar to prospective, except the operating firm will sell the product during the qualification runs, to the public as its market price. This validation involves in process monitoring of critical processing steps and product testing which helps to generate documented evidence to show that production process is in a state of control.
3) Retrospective validation: - In this historic data is taken from the records of the completed production batches are used to provide the documented evidence that the process has been in state of control prior to the request for such evidence.
4) Revalidation: - It is the repetition of validation process or part of it. This is carried out when there is any change or replacement in formulation, equipment plan or site location, batch size and in the case of sequential batches that do not meet product specifications and is also carried out at specific time intervals in case of no changes.
Stages of process validation: - There are 3 Stages of process validation they are
Stage 1:- Process design or pre-qualification: The commercial process is defined during this stage based on the knowledge gained through development and scale up activities.
Stage 2:- Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing.
Stage 3:- Continued process verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
Tablets are comprises of mixture of active ingredients and excipients which are compressed or molded into a cylindrical or biconvex solid. The principle objective of this dosage form is to achieve a predictable therapeutic response to a drug which is included into a formulation which is capable of large scale manufacturing with reproducible product quality. Their cost is lowest of all the oral dosage forms. They are lightest and compact of all oral dosage form.
Identify the key physicochemical properties of the drug substance that need to be considered in developing the formulations of tablet, such as the following:
1. Solubility of the drug substance throughout the physiological pH range: - Depending on the solubility of the drug, a surfactant may be needed to enhance dissolution.
2. Particle size distribution and surface area: The particle size distribution of the drug may determine what grade of an excipient (e.g., microcrystalline cellulose) to use.
3. Morphology: If the drug is amorphous or has different polymorphs, certain excipients may be used to prevent conversion of the drug to other physical forms.
4. True and bulk density: An excipient (e.g., diluents) that has a similar bulk density as the drug may be selected to minimize segregation, especially with a direct compression formulation.
5. Material flow and compressibility: A free flowing, highly compressible material such as microcrystalline cellulose may be used for drugs with poor flow or compressibility properties.
6. Hygroscopicity: Special environmental working conditions may be required ensure that moisture is not picked up during material storage or handling and during the manufacture of the tablet dosage form.
6. Melting point: If the drug has a low melting point, a direct compression formulation may need to be developed instead of a wet granulation formulation to avoid drying the material and potentially melting or degrading the drug.
Strategy for the industrial process validation of tablet dosage form: -
1. The use of different lots of Raw material should be included.
2. Batches should be run in succession in different shifts and days.
3. Batches should be manufactured in equipments and facilities that are designed for the commercial manufacturing.
4. Critical process parameters should set within their operating Ranges and should not undergo upper and lower limits of these ranges during the operation.
5. Failure to meet the requirement of protocol with respect to the process input and output must be subjected to process qualification and subsequent revalidation.
Process validation protocol: - It is a written plan which states that how will be the validation conducted including test parameters, product characteristics, production and packaging equipments and the acceptance criteria. This document gives the critical steps of the manufacturing process that should be measured and allowable range of variability and the manner in which the system is to be tested. The validation protocol provides a synopsis of hope what is to be accomplished. It should list the selected process and control parameters. State the number of batches which are to be included in to a study and specify how the data once assembled and be treated for relevance. The date of approval of protocol should be noted down by the validation team. In the case where the protocol is altered or modified appropriate reasons for such change must be documented.
Process Evaluation and Selection: - Determine the unit operations needed to manufacture the tablets and their critical process parameters.
1. Mixing or Blending
The mixing or blending unit operation may occur once or several times during the tablet manufacture. For example, a direct compression formulation may involve one blending step in which the drug and the excipients are blended together prior to compression. A wet granulation formulation may require two mixing/blending steps: (1) prior to granulating to have a uniform drug/excipient mixture, and (2) after milling the dried granulation to add other excipients, such as the lubricant. Some or all the items provided in this section may therefore be pertinent for validation, depending on the mixing or blending objective.
The following physical properties of the drug and excipients are factor in creating a uniform mix or blend:
Particle size distribution
Materials that have similar physical properties will be easier to form a uniform mix or blend and will not segregate as readily as materials with large differences.
Mixing or blending technique: Diffusion (tumble), convection (planetary or high intensity), or pneumatic (fluid bed) techniques can be used to mix or blend materials. Determine the technique that is required for the formulation or process objective. It may be different, depending on whether you are mixing the drug and excipients for a direct compression formulation or adding the lubricant (e.g., magnesium stearate) to the granulation.
Mixing or blending speed: Determine the intensity (low/high shear) and/or speed (rpm) of the mixing or blending. Mixing the drug and excipient will require more intense mixing than adding the lubricant to the final blend.
Mixing or blending time: How much mixing or blending is required to obtain a uniform mixture? The mixing or blending time will be dependent on the mixing or blending technique and speed. Experiments should be done to determine if the materials can be over mixed, resulting in demixing or segregation of the materials. Demixing can occur due to the physical property differences (e.g., particle size distribution and density). For example, demixing can occur in a direct compression formulation in which the drug substance is micronized (5 microns) and the excipients are granular (500–1000 microns).
Drug uniformity: Content uniformity is usually performed to determine the uniformity of drug throughout the mix or blend. Representative samples should be taken throughout the mix or blend. The sampling technique and handling of the materials are key in obtaining valid content uniformity results. Segregation of the sample can occur by over handling, resulting in inaccurate results. For the final blend (blend prior to compression), the sample taken should be equivalent to the weight of a single tablet.
Excipient uniformity: Besides drug uniformity, excipients need to be uniform in the granulation or blend. Two key excipients are:
Lubricant: The lubricant needs to be distributed uniformly in the mixture/granulation for the high-speed compression operation. Uneven distribution of the lubricant can result in picking and sticky problems during compression. It can also lead to tablet performance problems (low dissolution due to excessive lubricant in some tablets).
Color: The colorant(s) need(s) to be evenly distributed in the mixture so that the tablets have a uniform appearance (e.g., color, hue, and intensity). The coloring agent may need to be prescreened or more uniformly dispersed in the blend prior to compression to avoid speckling or shading of the color.
Equipment capacity/load: The bulk density of materials or granules will affect the capacity of the equipment. If an excipient in the formulation affects the density of the final blend to a greater extent than any other ingredient, then a well-controlled density specification for that excipient may be warranted. Test different-sized loads in the mixer/ blender (e.g., 30, 50, and 70% of working volume) for optimal mixing or blending. Undercharging or overcharging a blender can result in poor drug or tablet lubricant distribution.
2. Wet Granulation
What type of wet granulation technique will be used? Will it be low shear (e.g., Hobart), high shear (e.g., Diosna, GEI-Collette) or fluid bed (e.g., Glatt, Fluid Air)? Each technique will produce granules with different physical properties and will require monitoring of different processing parameters. Wet granulation parameters to be considered during development and validation are:
Binder addition: Should the binder be added as a granulating solution or dry like the other excipients? Adding the binder dry avoids the need to determine the optimal binder concentration and a separate manufacture for the binder solution.
Binder concentration: The optimal binder concentration will need to be determined for the formulation. If the binder is to be sprayed, the binder solution needs to be dilute enough so that it can be pumped through the spray nozzle. It should also be sufficiently concentrated to form granules without over wetting the materials.
Amount of binder solution/granulating solvent: How much binder or solvent solution is required to granulate the material? Too much binder or solvent solution will overwet the materials and prolong the drying time. The amount of binder solution is related to the binder concentration.
Binder solution/granulating solvent addition rate: Define the rate or rate range at which the binder solution or granulating solvent can be added to the materials. Can the granulating solution be dumped into the mixer or does it have to be metered in at a specific rate?
Mixing time: How long should the material is mixed to ensure proper formation of granules? Should mixing stop after the addition of the binder or solvent solution or should additional mixing be required? Granulations that are not mixed long enough can form incomplete or weak granules. These granules may have poor flow and compression properties. On the other hand, over mixing the granulation can lead to harder granules and a lower dissolution rate.
Granulation end point: How is the granulation end point determined? Is it determined or controlled by granulation end point equipment (e.g., ammeter or wattmeter)? Is it controlled by specifying critical processing parameters? For example, a drug or excipient mixture may be granulated by adding a predetermined amount of water (granulating solution) at a certain rate. The granulation is completed after mixing for a set time after the water has been added.
3. Wet Milling
Does the wet granulation need to be milled to break up the lumps and enhance drying of the granulation? Wet granules that have a wide aggregate range can lead to inefficient drying (long drying times and partially dried large granules or lumps). Factors to consider are: critical process parameters which are needed to be considered during wet milling in process validation are.
1. Equipment size and capacity: The mill should be large enough to delump the entire batch within a reasonable time period to minimize manufacturing time and prevent the material from drying during this operation.
2. Screen size: The screen needs to be small enough to delump the material, but not too small to cause excessive heating of the mill, resulting in drying of the granulation.
3. Mill speed: The speed should be sufficient to efficiently delump the material without straining the equipment.
4. Feed rate: The feed rate of the wet granulation is interrelated to screen size and mill size and speed.
The type of drying technique (e.g., tray, fluid bed, and microwave) required for the formulation needs to be determined and justified. The type of technique may be dependent on such factors as drug or formulation properties and equipment availability. Changing dryer techniques could affect such tablet properties as hardness, disintegration, dissolution, and stability. The optimal moisture content of the dried granulation needs to be determined. High moisture content can result in (1) tablet picking or sticking to tablet punch surfaces and (2) poor chemical stability as a result of hydrolysis. An over dried granulation could result in poor hardness and friability. Moisture content analysis can he performed using the conventional loss-on-drying techniques or such state-of-the-art techniques as near infrared (NIR) spectroscopy. Parameters to consider during drying are:
Inlet/outlet temperature: The inlet temperature is the temperature of the incoming air to the dryer, while the outlet temperature is the temperature leaving the unit. The inlet temperature is critical to the drying efficiency of the granulation and should be set high enough to maximize drying without affecting the chemical/physical stability of the granulation. The outlet temperature is an indicator of the granulation temperature and will increase toward the inlet temperature as the moisture content of the granulation decreases (evaporization rate).
Airflow: There should be sufficient airflow to ensure removal of moisture laden air from the wet granulation. Insufficient airflow could prolong drying and affect the chemical stability of the drug. Airflow and the inlet/outlet temperature are interrelated parameters and should be considered together.
Moisture uniformity: The moisture content could vary within the granulation. Heat uniformity of the dryer (e.g., tray), amount of granulation per tray, and incomplete fluidization of the bed are factors that could affect the moisture uniformity of the granulation.
Equipment capability/capacity: The load that can be efficiently dried within the unit needs to be known. A larger load will require more moisture to be removed on drying and will affect the drying time. In the case of fluid bed drying, a maximum dryer load is that load above which the dryer will not fluidize the material.
The milling operation will reduce the particle size of the dried granulation. The resultant particle size distribution will affect such material properties as flow, compressibility, disintegration, and dissolution. An optimal particle size/size distribution for the formulation will need to be determined. Factors to consider in milling are:
Mill type: What mill type (e.g., impact or screen) should be used? Each has several variants, depending on the means to reduce the particles. The type of mill can generate a different particle size/size distribution. Particle size testing will need to be conducted and the results examined when substituting mill types.
Screen size: The selected screen size will affect the particle size. A smaller screen size will produce a smaller particle size and a greater number of fines.
Mill speed: What is the optimal mill speed? A higher mill speed will result in a smaller particle size and possibly a wider particle size distribution. It can also generate more heat to the product, depending on the screen size and feed rate, which could affect the stability of the product.
Feed rate: The feed rate is dependent on the mill capacity, screen size, and mill speed.
6. Tablet Compression
Compression is a critical step in the production of a tablet dosage form. The materials being compressed will need to have adequate flow and compression properties. The material should readily flow from the hopper onto the feed frame and into the dies. Inadequate flow can result in “rat holing” in the hopper and/or segregation of the blend in the hopper/feed frame. This can cause tablet weight and content uniformity problems. As for the compressibility properties of the formulation, it should be examined on an instrumented tablet press. Factors to consider during compression are as follows:
Tooling: The shape, size, and concavity of the tooling should be examined based on the formulation properties and commercial specifications. For intagliated (embossed) tablets, factors such as the position of the intagliation on the tablet and the intagliation depth and style should be examined to ensure that picking of the intagliation during compression or fill-in of the intagliation during coating does not occur.
Compression speed: The formulation should be compressed at a wide range of compression speeds to determine the operating range of the compressor. The adequacy of the material’s flow into the dies will be determined by examining the tablet weights. Is a force feeder required to ensure that sufficient material is fed into the dies?
Compression/ejection force: The compression profile for the tablet formulation will need to be determined to establish the optimal compression force to obtain the desired tablet hardness. The particle size/size distribution or level of lubricant may need to be adjusted in order to have a robust process on a high-speed compressor.
7. Tablet Coating
Tablet coating can occur by different techniques (e.g., sugar, film, or compression). Film coating has been the most common technique over recent years and will be the focus of this section. Key areas to consider for tablet coating include the following:
Tablet properties: Tablet properties such as hardness, shape, and intagliation (if required) are important to obtain a good film-coated tablet. The tablet needs to be hard enough to withstand the coating process. If tablet attrition occurs, the tablets will have a rough surface appearance. For tablet shape, a round tablet will be easier to coat than tablets will multiple sides or edges because of the uniformity of the surface. For intagliated tablets, the intagliation style and depth should be developed to prevent fill-in or chipping of the intagliation.
Equipment type: The type of coater will need to be selected. Conventional or perforated pan and fluid bed coaters are potential options.
Coater load: What is the acceptable tablet load range of the equipment? Having too large a pan load could cause attrition of the tablets because of the overall tablet weight in the coater. In the case of a fluid bed coater, there may not be sufficient airflow to fluidize the tablets.
Pan speed: What is the optimal pan speed? This will be interrelated to other coating parameters, such as inlet temperature, spray rate, and flow rate.
Spray guns: The number and types of guns should be determined in order to efficiently coat the tablets. The spray nozzles should be sized properly to ensure even distribution over the tablet bed and to prevent clogging of the nozzles. The location and angle of the spray gun(s) should be positioned to get adequate coverage. Having the guns positioned too close together can lead to a portion of the tablets to be over wet.
Application/spray rate: The optimal application/spray rate should be determined. Spraying too fast will cause the tablets to become over wet, resulting in clumping of tablets and possible dissolution of the tablet surface. Spraying too slowly will cause the coating materials to dry prior to adhesion to the tablets. This will result in a rough tablet surface and poor coating efficiency.
Tablet flow: The flow or movement of the tablets in the coater should be examined to ensure proper flow. There should be sufficient tablet bed movement to ensure even distribution of the coating solution onto the tablets. The addition of baffles may be required to provide adequate movement of tablets for tablet coating.
Inlet/outlet temperature and airflow: These parameters are interrelated and should be set to ensure that the atomized coating solution reaches the tablet surface and then is quickly dried.
Coating solution: The concentration and viscosity of the coating solution will need to be determined. The solution will need to be sufficiently diluted in order to spray the material on the tablets. The concentration of the coating solution will also determine the amount and volume of solution to be applied to the tablets. The stability of the coating solution should be investigated to establish its shelf life.
Coating weight: A minimum and maximum coating weight should be established for the tablet. Sufficient coating material should be applied to the tablets to provide a uniform appearance; however, it should not be great enough to cause fill-in of the intagliation.
Residual solvent level: If solvents are used for tablet coating, the residual solvent level will need to be determined.
Appearance testing of the tablets is critical during the coating operation. Items to look for include the following:
1. Cracking or peeling of the coating.
2. Intagliation fill-in.
3. Surface roughness.
4. Color uniformity.
Coating efficiency should be determined for the coating operation. The efficiency will determine the amount of coating solution overage that may be required.
1. Moisture content of “dried granulation”: Loss on drying (LOD) can be used to determine whether or not the granulation solvent has been removed to a sufficient level during the drying operation (usually less than 2% moisture).
2. Granulation particle size distribution: An extremely important parameter that can affect tablet compressibility, hardness, thickness, disintegration, dissolution, weight variation, and content uniformity. This parameter, which can be done by sieve analysis, should be monitored throughout the tablet validation process.
3. Blend uniformity: Samples of the blend are taken and analyzed to ensure that the drug is uniformly dispersed throughout the tablet/capsule blend. The proper blend time must be established so that the blend is not under- or over mixed. The sampling technique is critical for this test to be valid.
4. Individual tablet: the weight of individual tablets is determined throughout compression/encapsulation to ensure that the material is flowing properly and the equipment is working consistently. The individual weight should be within 5% of the nominal weight. Weight fluctuations or frequent machine adjustments suggest that the formulation/process (e.g. poor granulation flow) is not optimized and/or that the equipment may need maintenance.
5. Tablet hardness: Tablet hardness is determined periodically throughout the batch to ensure that the tablets are robust enough for coating, packing, and shipping and not too hard to affect dissolution.
6. Tablet thickness: Tablet thickness is also determined periodically throughout the batch and is indirectly related to the hardness. It is another indication of whether or not the formulation has proper flow and compression properties.
7. Disintegration: Disintegration is determined during the manufacture as a predictor of tablet performance
B. Finished Product Tests
1. Appearance: The tablets should be examined for such problems as tablet mottling, picking of the monogram, tablet filming, and capping of the tablets. If the tablets are colored, the color quality needs to be examined.
2. Assay: This test will determine whether or not the product contains the labeled amount of drug.
3. Content uniformity: Samples are taken across the batch profile (beginning, middle, and end) and analyzed to ensure that the dosage forms comply with compendial standards (}15% of the labeled amount) or more stringent internal limits. It will indicate whether there is demixing during the manufacturing operation (i.e., segregation during flow of granulation from a storage bin).
4. Tablet hardness: A critical parameter for dosage form handling and performance.
5. Tablet friability: Friability is an important characteristic on the tablets’ ability to withstand chipping, cracking, or “dusting” during the packaging operations and shipping.
6. Dissolution: Dissolution is important to ensure proper drug release characteristics (in vitro availability) and batch-to-batch uniformity.
Tablet dosage form should be integral part of the comprehensive validation program me within the industry. The total program me should begin with the validation of API so that material will remain uniform from batch to batch. The scientific information which is obtained during the preformulation stage can form the basis for the validation program me Validation of a new or existing product involves the efforts of scientists at various stages of the product development life cycle. Scientific information obtained during the preformulation stage can form the basis for a well-designed and comprehensive validation program. Continued awareness of validation requirements and a diligent application of validation principles will thus help to ensure that pharmaceutical products will be able to be developed and produced with the quality and reproducibility required from regulatory agencies across the world.
1. U.S. Food and Drug Administration. Guideline on General principles of Process Validation. Rockville, MD; May, 1987.
2. Nash RA, Watcher AH. Pharmaceutical Process Validation. 3rd Ed. New York: Marcel Dekker, INC;1990. P.159-180.
3. Mehta R.M. Processing of tablets, Pharmaceutics-1. Delhi: Vallabh prakashan; 2002.P.238-267.
4. U.S. FDA. Guideline on general principles of process validation. Guide Indus May (1987).
5. Rippie, E. G. Mixing. In: L. Lockman, H. Lieberman, I. Kanig, eds. Theory and Practice of Industrial Pharmacy. 2nd ed. Philadelphia: Lea & Febiger, pp. 486–502(1976).
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